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Structures of α-synuclein filaments from multiple system atrophy

DOI: 10.1038/s41586-020-2317-6 DOI Help

Authors: Manuel Schweighauser (MRC Laboratory of Molecular Biology) , Yang Shi (MRC Laboratory of Molecular Biology) , Airi Tarutani (Tokyo Metropolitan Institute of Medical Science; The University of Tokyo) , Fuyuki Kametani (Tokyo Metropolitan Institute of Medical Science) , Alexey G. Murzin (MRC Laboratory of Molecular Biology) , Bernardino Ghetti (Indiana University School of Medicine) , Tomoyasu Matsubara (Tokyo Metropolitan Institute of Gerontology) , Taisuke Tomita (The University of Tokyo) , Takashi Ando (Nagoya University Graduate School of Medicine) , Kazuko Hasegawa (Sagamihara National Hospital) , Shigeo Murayama (Tokyo Metropolitan Institute of Gerontology) , Mari Yoshida (Aichi Medical University) , Masato Hasegawa (Tokyo Metropolitan Institute of Medical Science) , Sjors H. W. Scheres (MRC Laboratory of Molecular Biology) , Michel Goedert (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 585 , PAGES 464 - 469

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 17434

Abstract: Synucleinopathies, which include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases1. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells2,3. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies4,5,6,7,8,9, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.

Journal Keywords: Cryoelectron microscopy; Neurodegeneration

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

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